The subject matter of the invention are S-substituted 2-azido-3-mercapto-propionic acid esters of the general formula: ##STR2## in which R.sup.1 is a methyl or ethyl group and R.sup.2 is an unsubstituted or substituted alkyl group, a cycloalkyl group, an unsubstituted or substituted aromatic or heteroaromatic group or a benzyl group, and a process for their production by reaction of a methyl or ethyl ester of 2-chloroarcyclic acid of the general formula: ##STR3## where R.sup.1 is a methyl or ethyl group with a thiol of the general formula: EQU R.sup.2 --S--H (III)
in which R.sup.2 is as defined above to form an S-substituted 2-chloro-3-mercapto-propionic acid ester of the general formula: ##STR4## in which R.sup.1 and R.sup.2 are as defined above and subsequently exchanging the chlorine atom with an azido group by means of an alkali metal azide (e.g. sodium azide or potassium azide) in the presence of a phase transfer catalyst.
The compounds of general formula (I) are valuable intermediate products for the production of D,L-cysteine and S-substituted derivatives of D,L-cysteine.
Therefore, a further purpose of the invention is the use of S-substituted 2-azido-3-mercapto-propionic acid esters of general formula (I) as intermediate products in the production of D,L-cysteine or derivatives of D,L-cysteine.
The process for the production of the compounds of general formula (I) according to the invention starts from the readily accessible methyl or ethyl ester of the 2-chloroacrylic acid and in both reaction steps proceeds with high yields.
In the first reaction step the methyl or ethyl ester of 2-chloroacrylic acid is reacted with a thiol of general formula (III) to form an S-substituted 2-chloro-3-mercapto-propionic acid ester of general formula IV. Suitable thiols for example, are methyl mercaptan, ethyl mercaptan, n-propyl mercaptan, n-butyl mercaptan, n-pentyl mercaptan, n-hexyl mercaptan, isopropyl mercaptan, isobutyl mercaptan, secondary butyl mercaptan, n-octyl mercaptan, cyclopentyl mercaptan, cyclohexyl mercaptan, thioglycolic acid methyl ester thioglycolic acid ethyl ester, thioglycolic acid benzyl ester, thioglycolic acid octyl ester, 3-mercaptopropionic acid ethyl ester, thiophenol, 2-chlorothiophenyl, 3-chlorothiophenol, 4-chlorothiophenol, 2,4-dichlorothiophenol, 3,4-dichlorothiophenol, 3,5-dichlorothiophenol, 2-methylthiophenol, 4-methylthiophenol, 3,5-dimethoxythiophenol, 2-fluorothiophenol, 4-fluorothiophenol, 3-trifluoromethylthiophenol, 4-cyanothiophenol, 4-nitrothiophenol, 3-methylmercaptothiophenol, 2-mercaptopyrimidine, bis-(dimethylamino)-mercapto-s-triazine, bis-(dimethoxy)-mercapto-s-triazine, 2-amino-5-mercapto-1,3,4-thiadiazole, 2-methylamino-5-mercapto-1,3,4-thiadiazole, benzyl mercaptan, or dimercaptomethane. Thus there are employed for example, thiols of formula (III) where R.sup.2 is alkyl, e.g. of 1 to 8 carbon atoms, mercapto lower alkyl, carboxyalkyl, e.g. having 2 to 3 carbon atoms in the alkyl group, lower alkyl carboxyalkyl, benzyl, phenyl, halophenyl, e.g. having 1 or 2 halogen atoms, e.g. chlorine, bromine or fluorine, lower alkyl phenyl, e.g. mono or di lower alkyl phenyl, lower alkoxyphenyl, e.g. mono or di lower alkoxy phenyl, trifluoromethylphenyl, cyanophenyl, nitrophenyl, lower alkyl mercaptophenyl, pyrimidyl, bis-(dilower alkylamino)-s-triazinyl, bis-(dilower alkoxy)-s-triazinyl, amino-1,3,4-thiadiazolyl, lower alkylamino-1,3,4-thiadiazolyl.
The addition of the thiol to the 2-chloroacrylic acid ester suitably is carried out in an inert solvent, such as an aliphatic or aromatic hydrocarbon e.g. cyclohexane, benzene, or toluene; an ether, e.g. dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methyl-tert.butyl ether, diisopropyl ether or diethyl ether; a chlorinated hydrocarbon, e.g. methylene chloride, chloroform or 1,2-dichloroethane; or in special cases, also in water. However, the preferred solvent is methylene chloride. The reaction is carried out under the catalytic influence of the sodium or triethylammonium thiolate of the thiol employed, which thiolate advantageously can be formed in situ from the thiol and sodium or triethylamine. The sodium or triethylammonium thiolate is suitably added in an amount of 0.1 to 50 mole percent, preferably from 1 to 25 mole percent. The suitable temperature range for the reaction is between -40.degree. and +80.degree. C., especially between 0.degree. and 30.degree. C.
It is especially advantageous if there is present the 2-chloroacrylic acid ester together with at least a small part of the thiolate serving as catalyst in an inert solvent and the thiol, which in a given case contains the residual thiolate, slowly is added at room temperature, for example, in the course of 10 minutes up to one hour, and subsequently the mixture is stirred for a still longer time, for example, 10 minutes to 13 hours.
After the end of the reaction the solvent is drawn off under reduced pressure. The residue is taken up in diethyl ether and the undissolved thiolate remaining filtered off. After removal of the ether, at the end suitably in a high vacuum, there remains the S-substituted 2-chloro-3-mercapto-propionic acid ester formed as a yellow colored oil.
In the second reaction step subsequently the chloro atom of the S-substituted 2-chloro-3-mercapto-propionic acid ester of the general formula IV is exchanged with an azido group by means of an alkali metal azide. Preferably the exchange is carried out by means of sodium azide. The carrying out of the reaction suitably depends on the viscosity of the reacting S-substituted 2-chloro-3-mercapto-propionic acid ester. If this is of a relatively low viscosity the reaction is advantageously carried out in water, on the contrary if it is a relatively high viscosity oil, then it is better to carry out the reaction in acetonitrile. Since the reaction is suitably carried out at relatively low temperatures in the range between room temperature and 100.degree. C., for example at about 40.degree. to 60.degree. C., to avoid undesired side reactions, the presence of a phase transfer catalyst is necessary. There are suitable all of the phase transfer catalysts known in the literature, such as quaternary ammonium and phosphonium salts or crown ethers. Preferably there are used quaternary ammonium salts, especially a commercial tri-(C.sub.8 to C.sub.10 -alkyl)methyl ammonium chloride ("Tricaprylylmethylammonium chloride", Aliquat 336). The phase transfer catalyst is suitably used in an amount between 0.5 and 20 mole percent, preferably between 1.0 and 5 mole percent, based on the S-substituted 2-chloro-3-mercapto-propionic acid ester employed. The alkali metal azide is suitably employed in excess, for example in 1.1 to 1.5 times the theoretically required amount. The exchange of the chlorine atom with the azido group generally requires a reaction time of 7 to 12 hours. For the production of the most complete reaction possible it is important to see to it that there is good intermixing of the heterogeneous system. The isolation of the S-substituted 2-azido-3-mercapto-propionic acid ester formed having the general formula (I) is advantageously carried out in such manner that the crude reaction mixture is extracted several times with diethyl ether, the combined extracts dried, for example with magnesium sulfate, and a chromatographic separation undertaken in a silica gel column. As mobile phase for the separation diethyl ether is especially suited.
In this chromatographic separation surprisingly impurities or by products are retained in the silica gel column so that the eluate after evaporation, suitably at reduced pressure, yields a colorless oil which according to its elemental analytical and spectroscopic data consists of the pure S-substituted 2-azido-3-mercapto-propionic acid ester of the general formula (I).
Then through the reduction of the azido group there can be produced from these new compounds the corresponding S-substituted D,L-cysteine esters. Since it is a matter of sulfur containing compounds the customary catalytic processes used for the reduction of azido groups are not suitable because the catalysts are very quickly poisoned.
The compounds of the general formula (I), however, can be reduced with hydrogen sulfide in a mixture of equal parts by volume of pyridine and water at room temperature within short reaction times of, for example, 2 hours to form the corresponding S-substituted D,L-cysteine esters.
It is more advantageous to undertake the reduction of the S-substituted 2-azido-3-mercapto-propionic acid ester by means of hydrogen in the presence of rhenium (VII) sulfide. The hydrogenation can be carried out in the temperature range between 20.degree. and 100.degree. C. without excess pressure or at hydrogen pressures up to 100 bar. Suitable solvents for the hydrogenation reaction are aqueous hydrochloric acid having a concentration between 0.1N and 10N, solutions of gaseous hydrogen chloride in a lower alkanol, e.g. methanol, ethanol, or isopropanol, or acetic anhydride. Depending on the reaction conditions used there are obtained as reaction products the corresponding S-substituted D,L-cysteine ester hydrochlorides, the corresponding S-substituted D,L-cysteine hydrochlorides or the corresponding S-substituted N-acetyl-D,L-cysteines.
Then in a known manner the methyl or benzyl group can readily be split off from the S-methyl or S-benzyl-D,L-cysteine hydrochloride so that there is obtained D,L-cysteine in good yield.
The processes can comprise, consist essentially of, or consist of the stated steps with the recited materials.
Unless otherwise indicated all parts and percentages are by weight.
The invention is explained in more detail through the following examples.